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Gene therapies are another milestone in the progression from one‐size‐fits‐all medicine to personalized medicine. Much of this progress has been made in oncology where molecular diagnostics are part of the drug development process and predictive biomarkers are used to guide treatment. By 2018, there were 21 different drugs that had been approved alongside companion diagnostics by the USFDA with testing requirements as part of their labeled approval. Of the drugs with required companion diagnostic tests, nearly half are for treatments of non‐small cell lung cancers (NSCLC).²⁸

In 2004, epidermal growth factor receptor (EGFR) mutations were identified to have predictive potential. In subsequent years, ALK and ROS mutations would also be identified to further direct cancer treatment based on the types of mutations present in the lung tumors.²⁹ A decade later, Opdivo^® (nivolumab) and Keytruda^® (pembrolizumab) were the first programmed death 1 (PD‐1) and programed death‐ligand 1 (PD‐L1) inhibitors approved. PD‐1 is a checkpoint protein found on T cells and these drugs cause the patient's immune system to attack cancer. Both these drugs are IgG humanized, mAbs that work by binding to the PD‐1 receptor and blocking its interaction with PD‐L1 and PD‐L2 ligands; blocking PD‐1 activity has resulted in decreased tumor growth in clinical trials. There are multiple drugs currently marketed for inhibiting the PD‐1 system, and most have companion diagnostics that look for PD‐L1 ligand expression to direct use. Additionally, patients with certain cancers are tested for other tumor mutations, which may indicate that a different drug should be tried first before a PD‐1 inhibitor. For example, the FDA‐labeled indication as a single agent for metastatic NSCLC for Keytruda^® includes the following:

KEYTRUDA^®, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD‐L1 (TPS ≥ 1%) as determined by an FDA‐approved test, with disease progression on or after platinum‐containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA‐approved therapy for these aberrations prior to receiving KEYTRUDA^®.³⁰

As this labeling indicates, patients are directed to use an FDA‐approved test to determine their PD‐L1 expression. If they have EGFR or ALK mutations, they are to try other targeted therapies first (e.g. drugs to treat EGFR or ALK mutations) before using Keytruda^®, which targets PD‐L1. These types of treatment pathways are becoming synonymous with precision medicine and the impact to the healthcare system is significant. Reimbursement groups welcome the ability to better predict that the medicines being paid for will work, and clinicians and patients welcome the potential for improved health outcomes based on more specific science. Precision medicine, however, will not progress into the future without challenges. The remainder of this chapter will focus on clinical and market‐related challenges with biologic drugs in precision medicine.